Overexpression Of TrkB Research Articles

TrkB Promotes Metastases

In a screen for proteins that would prevent rat intestinal epithelial cell death caused by loss of cell attachment, so-called anoikis, Douma et al. identified the neurotrophin receptor tyrosine kinase TrkB. Further analysis showed that overexpression of TrkB with or without coexpression of its ligand, brain-derived neurotrophic factor (BDNF), prevented apoptosis in response to transfer of cells from an attached culture condition to a detached culture condition. Furthermore, engineered cells expressing luciferase (to allow noninvasive imaging) and TrkB with or without coexpression of BDNF were highly metastatic and tumorigenic when injected (subcutaneously or intravenously) into nude mice. TrkB appeared to mediate its cell survival effects by stimulating the phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB) pathways. However, the downstream effectors remain unknown. Inhibition of mTOR (mammalian target of rapamycin), Rac, or mitogen and extracellular signal-regulated protein kinase (MEK) failed to block the survival effects of TrkB. The implications of these results for cancer therapy and prognosis are discussed by Liotta and Kohn. S. Douma, T. Van Laar, J. Zevenhoven, R. Meuwissen, E. Van Garderen, D. S. Peeper, Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature 430 , 1034-1039 (2004). [Online Journal] L. A. Liotta, E. Kohn, Anoikis: Cancer and the homeless cell. Nature 430 , 973-974 (2004). [Online Journal]

Increased expression of neurotrophins and their receptors in the mechanically compressed spinal cord of the spinal hyperostotic mouse (twy/twy)

The purpose of the present study was to identify any compensatory changes at the site of chronic compression of the spinal cord and neighboring segments. For this purpose, serial immunohistochemical and immunoblot analyses were performed for the expression levels of endogenous brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3, and their receptors, trkB and trkC in 24 tip-toe walking Yoshimura mice (twy/twy) aged 12-24 weeks. The twy mouse exhibits spontaneous calcified deposits posteriorly at the C1-C2 level, compressing the spinal cord. Immunoreactivities for BDNF, NT-3, trkB and trkC were preferentially localized in the gray matter, particularly in the anterior horn cells. In 24-week-old twy mice with severe compression, expression levels of these neurotrophins at the site of maximal compression were significantly lower than at the less- or non-compressed sites. In contrast, the expression levels of BDNF, NT-3, trkB and trkC were significantly higher at the rostral and caudal sites immediately adjacent to the maximal compression site. No such changes were noted in 12-week-old twy mice or in control Institute of Cancer Research mice. Our results suggest that overexpression of BDNF, NT-3, trkB and trkC in motoneuron areas neighboring the site of mechanical compression may represent compensatory changes in response to the compromised neuronal function at the level of compression, and that these proteins possibly contribute to neuronal survival and plasticity.

Exacerbated status epilepticus and acute cell loss, but no changes in epileptogenesis, in mice with increased brain-derived neurotrophic factor signaling

Several studies suggest that brain-derived neurotrophic factor (BDNF) can exacerbate seizure development during status epilepticus (S.E.) and subsequent epileptogenesis in the adult brain. On the other hand, evidence exists for the protective effect of BDNF. To study this controversy, we induced S.E. with kainate in transgenic mice with increased BDNF signaling due to trkB overexpression. Transgenic mice experienced a more severe S.E. than wild type animals did. Furthermore, they had increased acute hippocampal neuronal loss when assessed at 48 h after S.E. The effect of trkB overexpression on the development of epilepsy, chronic neuronal death, mossy fiber sprouting, and neurogenesis were studied at 4.5 months after kainate-induced S.E. No differences were found in the rate of epileptogenesis, severity of epilepsy, or cellular markers of network reorganization between transgenic and wild type mice. No differences between genotypes were observed in TUC-4 staining, indicating no effect of trkB overexpression to immature neuron numbers. Instead, in Cresyl Violet-stained preparations, the highest density of neurons was found in untreated transgenic mice suggesting a favorable effect of trkB overexpression on the survival of neurons in the hippocampus. Our data support the role of BDNF and trkB signaling in seizure generation and acute cellular damage after S.E. Long-term outcome was not, however, exacerbated by trkB overexpression.